Action to Cure Kidney Cancer

Bernard Escudier from Institut Gustave Roussy in Villejuif, France, made an oral presentation at a plenary session on a Phase 3 multi-center trial, called AVOREN, of the combination of Avastin/Interferon versus placebo/Interferon as a first-line therapy in metastatic kidney cancer. Dr. Escudier began his presentation by first explaining the rationale for this trial. Interferon is an immunotherapy that has shown modest benefits in kidney cancer, 4-6 months progression free survival (PFS) and over one year overall survival. Avastin inhibits VEGF, a promoter of angiogenesis.

Avastin has demonstrated activity in kidney cancer in two previous trials, one reported on by Jim Yang from the NIH in 2003, where PFS doubled from 2.5 months for a placebo to 4.8 months for Avastin. The second trial was reported by Ronald Bukowski from the Cleveland Clinic in 2006, where Avastin as a mono-therapy had a PFS of 8.5 months.

The AVOREN trial randomized patients to an Interferon/Avastin arm (327 patients) and an Interferon/placebo arm (322 patients). The Avastin dose was the standard 10 mg/kg every two weeks. There were 101 sites in 18 countries, excluding the US. The primary objective was to evaluate the efficacy of the Avastin combination based on overall survival. There were a number of secondary objectives.

The criteria for accepting patients included clear cell pathology, no prior treatment, no evidence of central nervous system metastasis, and not taking anti-coagulants. 85% were in the favorable or intermediate risk category.

The results were as follows (all the response data are reported by investigator assessment).

Dr. Escudier stratified the Progression Free Survival (PFS) results by risk status. The overall survival data may be confounded by the fact that as of the data cutoff, many patients were receiving other therapies. The results for these categories are.

Discontinuation from therapy due to adverse event was higher in the Interferon/Avastin arm (28%) than the Interferon/placebo arm (12%). Fatigue was the major grade 3/4 event in both arms being present at Interferon/Avastin (60%) and Interferon/placebo (45%).

Dr. Escudier concluded that the addition of Avastin to Interferon provides a statistically significant benefit toward PFS and tumor shrinkage with a trend toward improved overall survival in a well-tolerated combination of drugs.

Ronald Bukowski of the Cleveland Clinic was the discussant. His criticism of the study was that it didn't tell us what the effect of Avastin as a mono-therapy was. Given an overall response rate of 31% with the Interferon/Avastin arm versus 13% for the Interferon/placebo arm, was the improvement in response rate additive or synergistic? Secondly, for intermediate risk patients, the effect of Interferon is thought to be limited, so the 10.2 months response rate could possibly be attributed to Avastin alone. He also noted the increased toxicity of the combination arm. But in the end, he recommended adding Avastin, with or without Interferon, as an option to Sutent for treatment-naïve patients who are at good or intermediate risk. Dr. Bukowski didn't mention poor risk patients, but given the results, 2.2 months PFS, Torisel would be a better choice than Avastin - see Janice Dutcher's study, Correlation of Survival: Torisel versus Interferon, Subset Analysis, showing 5.1 months PFS for poor-risk patients.

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